Ocular Manifestations

Because many ophthalmologists and general practitioners may not be aware of the clinical ocular features of Lyme disease, ocular Lyme borreliosis is often underdiagnosed. Ocular manifestations can involve any of the ocular structures, and, while generally occurring in stage 2, they can occur at any stage either in the presence or absence of other organ involvement (Table 7.1). Ocular involvement, including conjunctivitis, periorbital edema, and mild photophobia, may be noted in as many as 11% of patients during the first stage of the disease [111]. Severe ophthalmic manifestations and intraocular inflammation first occur during stage 2. A number of conditions have been observed in later periods of stages 2 and 3, including stromal keratitis, granulomatous iridocyclitis with or without uveitis, intermediate uveitis, vitritis, panuveitis, retinitis, retinal vasculitis, choroiditis with or without serous retinal detachment, optic disk edema, optic neuritis, ischemic optic neuropathy, optic atrophy, ocular motor cranial neuropathies, Bell’s palsy, Argyll Robertson pupil, Horner’s syndrome, temporal arteritis, orbital myositis, and cortical blindness. In this chapter, we will evaluate retinal and choroidal changes in Lyme disease under the following headings:

1.Intermediate uveitis

2.Retinal vasculitis, branch retinal artery occlusion, and cotton-wool spots

3.Neuroretinitis

4.Choroiditis, chorioretinitis with or without serous retinal detachment

5.Miscellaneous: Cystoid macular edema and macular pucker, retinal pigment epithelial detachment, retinitis pigmentosa-like clinical presentation, choroidal neovascular membrane, acute posterior multifocal placoid pigment epitheliopathy (APMPPE)-like clinical presentation, retinal tear, and ciliochoroidal detachment

Intermediate Uveitis

Intermediate uveitis refers to inflammation localized to the anterior vitreous, pars plana, and peripheral retina. Infectious causes of intermedi-

ate uveitis are Epstein-Barr virus (EBV) infection, human T cell lymphotrophic virus type1 (HTLV-1) infection, cat scratch disease, hepatitis C, tuberculosis, and Lyme disease [117]. Lyme disease is a causative factor in 0.6% of all intermediate uveitis cases. Patients with intermediate uveitis due to Lyme disease typically present with complaints of floaters, blurred vision, or a vague, ill-defined disturbance of vision [118]. Involvement is usually bilateral, although asymmetric [117, 119]. Symptoms may often wax and wane over many months. The clinical picture most frequently seen is that of a syndrome resembling pars planitis complicated by posterior and granulomatous anterior chamber inflammation, which is inconsistent with classic intermediate uveitis, in which anterior chamber symptoms are not regularly encountered [120]. However, in some cases, the patient may present with mild anterior chamber reactions [121]. The hallmark of the disease is vitritis, which consists of vitreous cells that form aggregates, commonly referred to as snowballs, which are quite common and, although often noted in the inferior vitreous peripherally, may be found throughout the vitreous cavity. Inflammation of the pars plana may progress to form organized exudates called snowbanks. Inflammation-induced fibrovascular proliferation within the vitreous, vitreous base, and pars plana may result in retinal tears and rhegmatogenous retinal detachment [120]. However, intermediate uveitis in Lyme borreliosis can be seen even in the absence of severe ocular complaints [122].

Retinal Vasculitis, Branch Retinal Artery, Retinal Vein Occlusion, and Cotton-Wool Spots

Retinal vasculitis is a sight-threatening inflammatory disease that involves the retinal vessels. Retinal vasculitis may be either symptomatic or asymptomatic. If the retinal vascular changes occur in the periphery of the fundus without vitreous involvement, patients may have minimal or no symptoms. The condition results in sheathing and angiospasm, as well as arterial and/or venous occlusion. Inflammation of macular blood vessels can cause macular edema.

Retinal vasculitis due to Lyme disease was first presented in 1990 by Dr. U. Schonherr and associates at the International Conference on Borreliosis in Stockholm, Sweden, based on observing two individuals with this condition in a case series of ten patients. In 1991, Smith et al. published three cases of retinal vasculitis that were found to be seroreactive for Lyme borreliosis [123]. In the same year, Lang et al. reported a 43-year-old man admitted because of recurrent vitreous hemorrhage, who was diagnosed as bilateral occlusive retinal vasculitis with proliferative retinopathy due to Lyme disease with positive IgM and IgG serology for Borrelia burgdorferi [124]. In 1995, Leys et al. reported seven patients with retinal vasculitis due to Lyme disease with clinical and serologic evidence of Borrelia burgdorferi infection [125]. Three patients presented with abrupt loss of vision due to acute retinal vasculitis, and all demonstrated engorged veins, hemorrhages, perivenous infiltrates, and retinal white spots. Arterial occlusions were observed in two patients, and leakage was present from the veins, white spots, and the optic disk on fluorescein angiography. Four patients had signs of chronic uveitis with vitritis, cystoid macular edema, and retinal vasculitis, which were associated with neovascularization and vitreous hemorrhage in one patient and with optic neuritis in another patient [125]. Karma et al. reported a case series of ten ocular Lyme borreliosis patients in 1995 [126]. In this study, six of seven patients with uveitis had retinal vasculitis [126]. They extended this series to include an additional ten ocular Lyme borreliosis patients and published the series in 2000 [127]. Among the new patients in this extended series, two patients had evidence of retinal vascular involvement: one had peripheral multifocal chorioretinitis with panuveitis and the other had a branch retinal vein occlusion, possibly caused by a vasculitic mechanism as well [127]. Based on these results, they concluded that retinal vascular involvement in ocular Lyme borreliosis may be more common than previously thought [127].

Lightman et al. reported a branch retinal artery occlusion due to Lyme disease in a 37-year-old Caucasian woman [128]. The patient

presented with a scotoma above fixation in her left eye upon awakening. There was no known history of a tick bite or skin rash. The anterior segments were normal, and there was mild bilateral vitritis. The right optic nerve was slightly swollen, the retinal arterioles were irregular in caliber, and a cotton-wool spot was present above the disk. The left posterior segment had an inferotemporal branch retinal artery occlusion, ischemic whitening of the inferior macula, multiple cotton-wool spots, mild disk edema, and focal irregularity of some arterioles. FA demonstrated a branch retinal artery occlusion in the left eye and bilateral disk edema. Positive serological tests and clinical response to antibiotics made the diagnosis of ocular borreliosis [128]. The author proposed that an immunologic response to Borrelia burgdorferi causes vasculitis and obliteration of small vessels, as seen in connective tissue diseases, which are known to cause retinal arterial obstruction [128].

The pathogenesis of CWS is an occlusion of a feeder arteriole and capillaries, leading to vacuoles of various sizes and representing accumulated axoplasm in the nerve fiber layer due to ischemia. CWS in uveitis is often found not only in HIV infection but also in cytomegalovirus, tuberculosis, cryptococcal infection, Behcet’s disease, leptospirosis, and human T-lymphotropic virus type I. Klaeger et al. observed a 54-year- old woman who presented with recurrent iritis in her right eye and was diagnosed with ocular borreliosis and treated with doxycycline 100 mg bid for 3 weeks. After multiple recurrences of uveitis in her right eye, she presented with CWS in her left fundus (Fig. 7.2) and was treated with pentoxifylline 400 mg three times a day and salicylic acid 100 mg a day. The CWS gradually resolved but without proof that the resolution had been influenced by the therapy [129]. The patient Klaeger et al. presented differs from the Lightman et al. case in the absence of retinal whitening and focal irregularity of arterioles. Therefore, the only fundus finding of the Klaeger et al. case was CWS [129]. As a conclusion, Klaeger et al. advised ruling out ocular borreliosis in patients presenting with otherwise unexplained CWS [129].

Fig. 7.2 Fundus photograph from a patient with positive serology for Lyme disease showing multiple cotton-wool spots (CWS) in the left eye. All CWS are nearly equidistant from the optic disk, some are confluent, while some overlie major vessels (Reprinted with permission from Klaeger AJ, Herbort CP. Cotton wool spots as possible indicators of retinal vascular pathology in ocular lyme borreliosis. Int Ophthalmol. 2010 Oct;30(5):599–602. Epub 2008 Oct 15)

Neuroretinitis

Neuroretinitis typically presents in the form of white retinal lesions that may vary in size and topography. An associated mild or moderate vitreous inflammation is commonly observed. FA shows early hypofluorescence and late staining of large acute white retinal lesions and isofluorescence or moderate hypofluorescence of small active retinal lesions.

The first case of neuroretinitis due to Lyme disease was reported in a 13-year-old girl by Lesser and colleagues in 1990 [130]. Winterkorn et al. published another case of neuroretinitis due to Lyme in a 21-year-old girl in the same year [131]. Schönherr et al. reported a 22-year- old white female with bilateral Leber’s stellate neuroretinitis after a viral-like illness [132]. Seroconversion for Borrelia burgdorferi and resolution of symptoms and signs during therapy with 200 mg doxycycline resulted in a diagnosis of Lyme disease [132]. In a case series including ten patients, Karma et al. reported

four cases of neuroretinitis, three of which were bilateral and all accompanied by retinal vasculitis [126]. One year later, the same author reported a long-term follow-up of a chronic Lyme neuroretinitis that was unresponsive to systemic antibiotic therapy [133]. In 2001, Lochhead et al. reported a case of neuroretinitis due to Lyme disease in a 7-year-old girl that developed after bilateral papilledema and diagnosed by a positive Lyme IgG/M serology and cerebrospinal fluid PCR [134].

Choroiditis and Chorioretinitis with

or Without Serous Retinal Detachment

Choroiditis is the inflammation of the choroid. Inflammation may be diffuse, called multifocal choroiditis, or in patches, known as focal choroiditis. If the inflammation involves both the choroid and retina, it is named chorioretinitis. Typically, the only symptom is blurred vision.

The first case of bilateral multifocal choroiditis due to Lyme disease with exudative retinal detachment was reported by Bialasiewicz et al. in 1988 [135]. This case was a 32-year-old woman who was diagnosed with Vogt-Koyanagi- Harada disease and treated with oral corticosteroids by the referring ophthalmologist. At the presentation, bilateral inflammatory cells in the anterior chamber and vitreous, diffuse choroidal infiltration with exudative retinal detachment that extended peripherally between 4 o’clock and 8 o’clock, cystoid maculopathy, and choroidal thickening on B-scan ultrasonography were noted. However, diagnosis of bilateral diffuse choroiditis with exudative retinal detachment due to Lyme disease was made via demonstration of Lyme IgM antibodies in sera [135]. Wilk et al. also reported two cases of bilateral disseminated choroiditis with exudative retinal detachments in Borrelia burgdorferi infection [136]. In a survey of 84 Lyme arthritis patients, Huppertz et al. reported ocular inflammation in three of them [137]. One of the patients, a 13-year-old girl, presented with bilateral intermediate uveitis and right retinal detachment. A diagnosis of Lyme borreliosis was made when antibodies to Borrelia burgdorferi were detected in the patient’s serum; she was then treated with systemic tetracyclines.